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,,
*
Department of Surgery, Division of Biologic Therapeutics and Surgical Oncology,
Department of Pathology, and
University of Pittsburgh Cancer Institute, Pittsburgh, PA 15261; and
University of Pittsburgh Mass Spectrometry Facility, University of Pittsburgh Center for Biotechnology and Bioengineering, Pittsburgh, PA 15219
Induction of apoptosis in dendritic cells (DC) is one of the escape
mechanisms of tumor cells from the immune surveillance system. This
study aimed to clarify the underlying mechanisms of tumor-induced DC
apoptosis. The supernatants (SN) of murine tumor cell lines B16
(melanoma), MCA207, and MCA102 (fibrosarcoma) increased C16 and C24
ceramide as determined by electrospray mass spectrometry and induced
apoptosis in bone marrow-derived DC.
N-oleoylethanolamine or
D-L-threo
1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), which inhibits
acid ceramidase or glucosylceramide synthase and then increases
endogenous ceramide, enhanced DC apoptosis and ceramide levels in the
presence of tumor SN. Pretreatment with L-cycloserine, an
inhibitor of de novo ceramide synthesis, or phorbol ester,
12-O-tetradecanoylphorbol-13-acetate reduced endogenous
ceramide levels and protected DC from tumor-induced apoptosis. However,
other DC survival factors, including LPS and TNF-
, failed to do so.
The protective activity of
12-O-tetradecanoylphorbol-13-acetate is abrogated by
pretreatment with phosphoinositide 3-kinase (PI3K) inhibitor, LY294002.
Therefore, down-regulation of PI3K is the major facet of tumor-induced
DC apoptosis. Tumor SN, N-oleoylethanolamine, or PDMP
suppressed Akt, NF-
B, and bcl-xL in DC, suggesting that
the accumulation of ceramide impedes PI3K-mediated survival signals.
Taken together, ceramide mediates tumor-induced DC apoptosis by
down-regulation of the PI3K pathway.
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